The formation of a blood clot and its successive dissolution, referred to as the hemostatic process, is required to arrest blood loss from an injured vessel. This process is the result of a delicate functional balance between plasma coagulation factors (including fibrinogen), platelets, and fibrinolytic proteins. Each of these elements plays an important role in activating/deactivating the others, and the appropriate stimuli are necessary to prevent excessive blood loss without causing inappropriate thrombosis, see Laposata M., et al., The Clinical Hemostasis Handbook, Year Book Medical Publisher 1989.
The hemostatic process is initiated by the activation and subsequent adhesion of platelets to the site of injury within the vessel wall. Activated platelets recruit other platelets and interact with fibrinogen in the blood plasma via the glycoprotein IIb/IIIa receptor to form a platelet-plug that serves as the initial response to stop blood loss. Hemostasis then proceeds with a cascade of proteolytic reactions of the plasma coagulation proteins that ultimately form a three-dimensional network of fibrin that strengthens the platelet-plug. The fibrin chains are cross-linked and stabilized by the plasma factor XIIIa (FXIIIa). Platelets also have a central role in regulating the process of fibrin polymerization. The final step of hemostasis (i.e., fibrinolysis) involves the activation of the plasma protein plasmin, which dissolves the blood clot when its useful life is over. This cell-based model of hemostasis closely reflects the in vivo physiological process, e.g., see Hoffman et al., “A cell-based model of hemostasis;” Thromb. Haemost. 2001; 85:958-965 and Becker, “Cell-Based Models of Coagulation: A Paradigm in Evolution;” J. Thromb. Thrombolysis 2005: 20:65-68.
The mechanical properties of blood clots have implications for its function of stopping blood loss. Alterations in clot structure and its underlying mechanical properties have been implicated in thrombotic disease and other life threatening pathologies, see Weisel, J. W., “Enigmas of Blood Clot Elasticity;” Science 2008; 320:456. Recently, it was shown that fibrin clots of patients affected by premature coronary artery disease have a different structure and higher stiffness compared to the fibrin clots of healthy age-matched controls, see Collet et al, “Altered Fibrin Architecture is Associated with Hypofibrinloysis and Premature Coronary Atherothrombosis;” Arterioscler. Thromb. Vasc. Biol. 2006; 26:2567-2573.
The mechanics of fibrin networks have been studied extensively at the macroscopic level see Ryan et al., “Structural Origins of Fibrin Clot Rheology”; Biophys. J. 1999; 77:2813-2826 and Jen et al., “The Structural Properties and Contractile Force of a Clot;” Cell Motil. 1982; 2:445-455. The viscoelastic properties of individual fibrin strands have also been investigated by means of AFM (see Liu et al., “Fibrin Fibers Have Extraordinary Extensibility and Elasticity;” Science 2006; 313:634) and “optical tweezers,” see Collet et al., “The elasticity of an individual fibrin fiber in a clot;” Proc. Natl. Acad. Sci. USA 2005; 102:9133-9137.
Disruption of the hemostatic balance plays a role in the onset of potentially fatal conditions, including myocardial infarction, stroke, deep vein thrombosis, pulmonary embolism, and excessive bleeding, see Hoyert et al., “Deaths: preliminary data for 2003”, Natl. Vital Stat. Rep. 2005; 53:1-48 and Hambleton et al., “Coagulation: Consultative Hemostasis”; Hematology 2002; 1:335-352. These conditions account for over 30% of all deaths in the developed world. The ability to recognize and quantify defects of the hemostatic process may reduce mortality and implement appropriate treatment.
Further improvements in the detection and treatment of hemostatic defects are therefore desired.